Nonbenzodiazepine anticonvulsants

Definitions & Key takeaways

Nonbenzodiazepine anticonvulsants are a class of drugs used to treat seizures, headaches, and neuropathic pain. These drugs are also used as mood stabilizers for bipolar disorders. Nonbenzodiazepine anticonvulsants decrease excitatory signals in the brain, primarily by blocking sodium and calcium channels, or by enhancing the actions of GABA. This lead to a decrease in the abnormal electrical activity in the brain responsible for the associated symptoms.

Common examples of nonbenzodiazepine anticonvulsants include carbamazepine, lamotrigine, and valproic acid. Side effects include double vision, ataxia, and liver toxicity for carbamazepine; Stevens Johnson syndrome for lamotrigine; and teratogenic effects like neural tube defects for valproic acid.

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Introduction0:00–0:20

Anticonvulsants are a type of medication used to treat the various types of seizure disorders. These include benzodiazepines and barbiturates which increase the activity of inhibitory neurons, but there are also many other classes of anticonvulsants with different mechanisms that we’ll talk about in this video.Okay, so the cells that make up our brain are called neurons.

Physiology0:20–2:03

Neurons communicate with each other through neurotransmitters. When one neuron is stimulated, it releases excitatory neurotransmitters that bind to receptors on the next neuron.
This causes the next neuron to depolarize and release its own excitatory neurotransmitters, propagating the signal throughout the brain.The main excitatory neurotransmitter in our brain is glutamate which can bind to several types of receptors that are basically ligand-gated ion channels, which open up and allow Na+ and Ca2+ to flow in, and K+ to flow out.
In the end, when it’s all added up, there’s an influx of positive charge that makes the cell less negative,and the neuron becomes depolarized.
This causes nearby voltage-gated Na+ channels to open on the surface of the membrane, causing more Na+ to enter. This in turn triggers other nearby voltage-gated Na+ channels to open.So this series of depolarization travels down the neuron like a wave and it’s called an action potential.When it reaches the end of the neuron, called the synaptic terminal, it triggers the opening of voltage-gated Ca2+ channels, causing an influx of calcium ions which stimulates the release of neurotransmitters that are stored in synaptic vesicles.
Okay, we also have inhibitory neurons that shut down this chain of events. These neurons release the main inhibitory neurotransmitter called gamma-aminobutyric acid or GABA, which binds to GABA receptors on other neurons.
These GABA receptors are also ligand-gated ion channels, but they open up to let the negatively charged Cl-, into the cell.
The influx of negative ions causes hyperpolarization where the cell’s membrane potential becomes more negative, which means it’s much more difficult for it to depolarize and fire off an action potential.Alright, now there are cases where neurons in the brain start sending out more excitatory signals than normal.

Pathology2:03–3:15

This can occur due to either too much excitation or too little inhibition in the brain.Excessive excitatory signals can cause a variety of disorders like seizures and epilepsy.
Seizures are categorized based on the region of the brain that’s affected.When it’s limited to one hemisphere or a single lobe, we call it a focal or partial seizure, and these can cause the person to experience strange sensations, like hearing or tasting something that isn’t there, but can also involve jerking movements in specific muscle groups if the neurons controlling these muscles are affected.
A generalized seizure is where both hemispheres of the brain are affected. Tonic-clonic seizures are the most common generalized seizures, where patients experience a tonic phase, where the muscles suddenly tense up, followed by the clonic phase, where the muscles rapidly contract and relax.
Another type of generalized seizure is absence seizures, where the person has impaired awareness or responsiveness, generally with the only outward sign being that the person looks like they “spaced out.” If the seizures themselves last longer than 5 minutes without stopping, or if there are multiple seizures without returning to normal in between, then it’s called status epilepticus.Okay, so we can manage seizure disorders by increasing the effect of inhibitory neurons or decreasing the activity of excitatory neurons.

Voltage-gated sodium channel inhibitors3:15–7:25

Let’s start with a group of medications that block voltage-gated sodium channels, which inhibit the action potentials in excitatory neurons.
These include carbamazepine, valproic acid, phenytoin, lamotrigine, and topiramate. Some of these medications have other mechanisms as well.
Lamotrigine and topiramate inhibit the release of glutamate; and topiramate also inhibits voltage-gated calcium channels.
Valproic acid inhibits GABA transaminase, which is an enzyme that breaks down GABA in the inhibitory neurons. So valproic acid inhibits the metabolism of GABA, increases GABA concentration in the brain and enhances the effect of inhibitory neurons.
Okay moving on to indications. Carbamazepine, valproic acid, lamotrigine, topiramate and phenytoin are commonly used for the treatment of partial and generalized tonic-clonic seizures.
In addition, lamotrigine and valproic acid are used for absence seizures. For the prophylaxis of status epilepticus, phenytoin and its prodrug, fosphenytoin, are considered the medications of choice.
Apart from seizures and epilepsy, carbamazepine, lamotrigine, and valproic acid are also used as mood stabilizers for bipolar disorder.
Note also that carbamazepine is the first line treatment for trigeminal neuralgia which is a disorder characterized by shooting pain in the distribution of the trigeminal nerve.
Finally, valproic acid and topiramate are also used as prophylactic therapy for migraines and cluster headaches. Alright let’s move on to side effects.
Carbamazepine can cause diplopia or double vision, ataxia, agranulocytosis, liver toxicity, and SIADH or syndrome of inappropriate antidiuretic hormone secretion.
A rare but potentially fatal side effect of carbamazepine is Stevens Johnson syndrome, which is characterized by rapid desquamation of the skin.
Note also that carbamazepine is not safe to use during pregnancy because it increases the risk of congenital defects like cleft lip or palate, and neural tube defects such as spina bifida.
Also, carbamazepine induces a class of enzymes called cytochrome P450. These enzymes are involved in the metabolism of various medications like benzodiazepines, phenytoin, quinidine, warfarin, and others.
Increased cytochrome P450 activity can result in these medications being broken down too rapidly, so larger doses are needed to achieve a therapeutic effect.
Okay, now common side effects of lamotrigine include blurred vision and gastrointestinal symptoms, like nausea and vomiting.
If levels increase, lamotrigine can cause Stevens Johnson syndrome and thus serum levels should be monitored closely. Now side effects of phenytoin include visual disturbances like nystagmus, or involuntary eye movement; diplopia; ataxia; hirsutism or excessive hair growth; and gingival hyperplasia or enlarged gums.
Phenytoin also inhibits the absorption of folate in the small intestine and so it can lead to megaloblastic anemia. In addition, phenytoin induces cytochrome P450 just like carbamazepine.
Rare adverse effects include Stevens Johnson syndrome and symptoms that mimic systemic lupus erythematosus, or SLE-like syndrome.
Keep in mind that phenytoin is not safe to use during pregnancy. Teratogenic effects include intrauterine growth restriction or IUGR, intellectual disability, cleft lip or palate, and congenital heart defects.
Common side effects of valproic acid are gastrointestinal symptoms like nausea and vomiting, tremors, sedation, alopecia or loss of hair, weight gain, and blood disorders like a low platelet and white blood cell count.A rare but life-threatening adverse effect is liver toxicity.
Also note that valproic acid should not be used in pregnancy because it causes teratogenic effects like neural tube defects.
Finally, side effects of topiramate include sedation, kidney stones, weight loss, and visual disturbances like blurry vision, diplopia, and glaucoma.
Alright, let’s move on to calcium channel blockers which include ethosuximide, gabapentin, and levetiracetam. Ethosuximide is the drug of choice for absence seizures.

Calcium channel blockers7:25–8:18

Gabapentin is used for partial seizures, neuropathic pain in postherpetic neuralgia, fibromyalgia, peripheral neuropathy, and as a prophylaxis for migraines.
Levetiracetam has an unknown mechanism, but research suggests it works by blocking calcium channels and inhibiting glutamate release.
Now common side effects of ethosuximide include fatigue, gastrointestinal symptoms, headaches, and itching. Stevens Johnson syndrome is a rare adverse reaction.
Adverse effects of gabapentin include sedation and ataxia, while adverse effects of levetiracetam include sedation, fatigue, headaches, and changes in personality.

GABA inhibitors8:18–8:52

Finally, let’s move on to medications with mechanisms related to GABA, the main inhibitory neurotransmitter. Just like valproic acid, Vigabatrin inhibits GABA transaminase and thus enhances the effect of inhibitory neurons.
Another medication that increases GABA levels is tiagabine, which inhibits GABA reuptake from the synapse back to the neuron, and thus increases GABA concentration in the synapse.
Both vigabatrin and tiagabine can be used for the treatment of partial seizures. But what’s important is that vigabatrin can cause permanent bilateral visual loss!
Now, let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts about the miscellaneous anticonvulsants!

Memory Palace8:52–12:54

So first let’s use a grocery store to group them based on their main mechanisms of action. On the left most section, we have an aisle that only has salt to represent the sodium channel blockers, next we have a fridge section with milk for calcium channel blockers.
Finally we have a bin full of cabbages for the medications that increase the effect of GABA releasing inhibitory neurons.
Okay so let’s start by having a car crash into the salt aisle, and it explodes with a “BAM”, which represents carbamazepine.
The driver, who’s wearing a giant fanny pack, for phenytoin, gets out relatively unharmed. Next, let’s have the shocked valet, for valproic acid, who’s eating cabbage, since it also increases GABA level in the brain.Okay, next there’s a shocked pirate in a top hat for topiramate.
The crash caused him to break a lamp with three bulbs, for lamotrigine, and he’s trying to glue it back together. This will help you remember both these medications also inhibit glutamate release.
The pirate only drinks milk, to represent its inhibition of calcium channels. Now, it’s important to remember which medications can be used to treat absence seizures, so let’s turn the images for valproic acid and lamotrigine grey to represent the absence of color.
For some of the important side effects, let’s start with Stevens Johnson syndrome, which is represented by a two-headed zombies: the names of the heads are Steve and John.
These zombies are the cause of the crash so let’s have one attack the car and the man with the fanny pack, and one that’s attacking the lamp for some reason.
Now, fanny pack man managed to save one of his two babies. This baby has a cleft lip and a visible heart, to help you remember it could cause cleft lip and palate, and cardiac defects.
His other baby is still in the car and he’s got a cleft lip and a visible spine, for spina bifida. Because they can cause birth defects, both drugs are contraindicated during pregnancy.
Both drugs also induce cytochrome p450, so let’s put a chrome colored cell in the car and he managed to save the other. For some specific side effects of carbamazepine, let’s have another car crash into a silo, and grains are leaking out, which represent agranulocytosis.
There’s a damaged liver on top of the silo that’s about to fall off to represent the hepatotoxicity. A diaper is on top of the liver for SIADH.
Okay, for phenytoin, fanny pack man has a giant mustache for hirsutism, and he’s blowing bubble gum, for gum hypertrophy.
There’s a folder with important files that’s sticking out of his fanny pack to help you remember folate deficiency.He’s holding the leash to his pet wolf to represent Lupus-like syndrome.
Next, let’s look at the valet for valproic acid. He’s bald for alopecia, and he’s also carrying a baby with his spine showing, so it’s contraindicated during pregnancy.
Next to him, are a pile of broken dishes and dead white blood cells, to help you remember decreased platelets and WBC.There’s also a damaged liver in the pile for hepatotoxicity.
For the pirate, let’s give him a kidney stone to hold. His eyes are popping out at the shocking scene to represent glaucoma.
Phew, that was a lot! We can finally move onto the next class of drugs, which are the calcium channel blockers in the dairy section.Here let’s have a janitor named Ethan vacuuming the floor, and he represents ethosuximide.
Next to him, is an artist who’s painting a picture of a cabbage for gabapentin. This artist is sitting on a see-saw which acts like a lever for Levetiracetam.
Now, ethosuximide is the drug of choice for absence seizures, so let’s make him a lighter shade of grey. For major side effects, a Steve and John zombie snuck up behind the janitor but he couldn’t hear the danger due to the sound of the vacuum.Okay for the final section, let’s head to the cabbage bin, where we keep all the medications that mainly affect GABA releasing neurons.
So checking out the cabbages, we have a vegan bat for vigabatrin, and it’s wearing a tiara for tiagabine. For side effects, let’s cover the eyes of the bat in bandages to help you remember vigabatrin can cause permanent bilateral blindness.##SummaryAll right, as a quick recap… Nonbenzodiazepine anticonvulsants are used for the treatment of seizures, as mood stabilizers for bipolar disorder, and for pain relief in conditions like trigeminal neuralgia, neuropathic pain, and headaches.

Review12:54–13:30

They can decrease excitatory signals in the brain primarily by blocking sodium channels, calcium channels, or by enhancing the actions of GABA.
Carbamazepine and phenytoin induce cytochrome p450, and like the valproic acid, they’re not safe to use during pregnancy.
A rare but fatal side effect of anticonvulsants and especially of lamotrigine is Stevens-Johnson syndrome. But wait, there’s more: Here’s a mind map with all of the mnemonics.

Mind Map13:30–13:40

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.